Lateral needle-less injection apparatus and method

ABSTRACT

A device and method for delivering and injecting fluid into heart tissue utilizing laterally directed injection ports to increase injectate (fluid) retention in the heart tissue. The catheter includes a shaft having an infusion lumen extending therethrough, wherein the distal end of the shaft includes a penetrating member having one or more injection ports. The penetrating member penetrates the heart tissue in a first direction, and the injection port or ports direct fluid in a second direction different from the first direction. By injecting the fluid or fluid in a direction different than the penetration direction, fluid leakage from the injection site is reduced and a greater volume of tissue is treated for a single primary injection.

RELATED APPLICATIONS

This application is related to co-pending patent application Ser. No.09/457,453 filed on even date herewith entitled INJECTION ARRAYAPPARATUS AND METHOD, co-pending patent application Ser. No. 09/457,254filed on even date herewith entitled LATERAL NEEDLE INJECTION APPARATUSAND METHOD, and co-pending patent application Ser. No. 09/456,456 filedon even date herewith entitled NEEDLE-LESS INJECTION APPARATUS ANDMETHOD.

FIELD OF THE INVENTION

The present invention generally relates to delivering and injectingfluid into heart tissue. More specifically, the present inventionrelates to delivering and injecting fluid into heart tissue utilizinglaterally directed injection ports.

BACKGROUND OF THE INVENTION

Injection catheters may be used to inject therapeutic or diagnosticagents into a variety of organs, such as the heart. In the case ofinjecting a therapeutic agent into the heart, 27 or 28 gauge needles aregenerally used to inject solutions carrying genes, proteins, or drugsdirectly into the myocardium. A typical volume of an agent delivered toan injection site is about 100 microliters. A limitation to this methodof delivering therapeutic agents to the heart is that the injected fluidtends to leak from the site of the injection after the needle isdisengaged from the heart. In fact, fluid may continue to leak overseveral seconds. In the case of dynamic organs such as the heart, theremay be more pronounced leakage with each muscle contraction.

Therapeutic and diagnostic agents may be delivered to a portion of theheart as part of a percutaneous myocardial revascularization (PMR)procedure. PMR is a procedure which is aimed at assuring that the heartis properly oxygenated. Assuring that the heart muscle is adequatelysupplied with oxygen is critical to sustaining the life of a patient. Toreceive an adequate supply of oxygen, the heart muscle must be wellperfused with blood. In a healthy heart, blood perfusion is accomplishedwith a system of blood vessels and capillaries. However, it is commonfor the blood vessels to become occluded (blocked) or stenotic(narrowed). A stenosis may be formed by an atheroma which is typically aharder, calcified substance which forms on the walls of a blood vessel.

Historically, individual stenotic lesions have been treated with anumber of medical procedures including coronary bypass surgery,angioplasty, and atherectomy. Coronary bypass surgery typically involvesutilizing vascular tissue from another part of the patient's body toconstruct a shunt around the obstructed vessel. Angioplasty techniquessuch as percutaneous transluminal angioplasty (PTA) and percutaneoustransluminal coronary angioplasty (PTCA) are relatively non-invasivemethods of treating a stenotic lesion. These angioplasty techniquestypically involve the use of a guide wire and a balloon catheter. Inthese procedures, a balloon catheter is advanced over a guide wire suchthat the balloon is positioned proximate a restriction in a diseasedvessel. The balloon is then inflated and the restriction in the vesselis opened. A third technique which may be used to treat a stenoticlesion is atherectomy. During an atherectomy procedure, the stenoticlesion is mechanically cut or abraded away from the blood vessel wall.

Coronary by-pass, angioplasty, and atherectomy procedures have all beenfound effective in treating individual stenotic lesions in relativelylarge blood vessels. However, the heart muscle is perfused with bloodthrough a network of small vessels and capillaries. In some cases, alarge number of stenotic lesions may occur in a large number oflocations throughout this network of small blood vessels andcapillaries. The torturous path and small diameter of these bloodvessels limit access to the stenotic lesions. The sheer number and smallsize of these stenotic lesions make techniques such as cardiovascularby-pass surgery, angioplasty, and atherectomy impractical.

When techniques which treat individual lesion are not practical,percutaneous myocardial revascularization (PMR) may be used to improvethe oxygenation of the myocardial tissue. A PMR procedure generallyinvolves the creation of holes, craters or channels directly into themyocardium of the heart. In a typical PMR procedure, these holes arecreated using radio frequency energy delivered by a catheter having oneor more electrodes near its distal end. After the wound has beencreated, therapeutic agents are sometimes ejected into the heart chamberfrom the distal end of a catheter.

Positive clinical results have been demonstrated in human patientsreceiving PMR treatments. These results are believed to be caused inpart by blood flowing within the heart chamber through channels inmyocardial tissue formed by PMR. Increased blood flow to the myocardiumis also believed to be caused in part by the healing response to woundformation. Specifically, the formation of new blood vessels is believedto occur in response to the newly created wound. This response issometimes referred to as angiogenesis. After the wound has been created,therapeutic agents which are intended to promote angiogenesis aresometimes injected into the heart chamber. A limitation of thisprocedure is that the therapeutic agent may be quickly carried away bythe flow of blood through the heart.

In addition to promoting increased blood flow, it is also believed thatPMR improves a patient's condition through denervation. Denervation isthe elimination of nerves. The creation of wounds during a PMR procedureresults in the elimination of nerve endings which were previouslysending pain signals to the brain as a result of hibernating tissue.

Currently available injection catheters are not particularly suitablefor accurately delivering small volumes of therapeutic agents to hearttissue. Improved devices and methods are desired to address the problemsassociated with retention of the agent in the heart tissue as discussedabove. This is particularly true for agents carrying genes, proteins, orother angiogenic drugs which may be very expensive, even in small doses.

SUMMARY OF THE INVENTION

The present invention provides an improved apparatus and method fordelivering and injecting fluid into heart tissue. The present inventionaddresses the problems associated with retention of the fluid in theheart tissue by utilizing one or more laterally directed injectionports. The present invention may be used to deliver genes, proteins, ordrugs directly into the myocardium for purposes of myocardialrevascularization.

In an exemplary embodiment, the present invention provides a catheterhaving a shaft with an infusion lumen extending therethrough. The distalend of the shaft includes a penetrating member having one or moreinjection ports. The penetrating member penetrates the heart tissue in afirst direction, and the injection port or ports direct fluid in asecond direction different from the first direction. By injecting thefluid or fluids in a direction different than the penetration direction,fluid leakage from the injection site is reduced and a greater volume oftissue is treated for a single primary injection.

The injection ports may have a diameter of approximately 1 to 500microns, depending on the desired injection parameters. The seconddirection may be at an angle of about 5 to about 90 degrees relative tothe first direction, and the first direction is preferably orthogonal tothe heart tissue at the injection site.

The catheter may include a sheath disposed about the shaft. The distalend of the sheath may include a suction head for stabilizing the distalend of the catheter upon the application of suction to the sheath.

The present invention also provides a method of delivering a fluid toheart tissue including the steps of: navigating a catheter substantiallyas described above in a patient's body until the distal end of thecatheter is positioned adjacent the injection site; actuating thepenetrating member such that the penetrating member penetrates the hearttissue in a first direction; and injecting the fluid into the hearttissue via the injection ports at a second direction different than thefirst direction. This method reduces fluid leakage from the injectionsite and treats a greater volume of tissue for a single primaryinjection.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a plan view of a catheter system in accordance with anexemplary embodiment of the present invention;

FIG. 1B is an enlarged detailed view of the distal end of the catheterillustrated in FIG. 1A;

FIG. 2 is a further enlarged view of the distal end of the catheterillustrated in FIG. 1A;

FIG. 3 is a lateral cross-sectional view taken along line 3—3 in FIG. 2;

FIG. 4 is a lateral cross-sectional view taken along line 4—4 in FIG. 2;

FIG. 5 is a simplified longitudinal cross-sectional view of thepenetrating member;

FIGS. 6A-6C illustrate a sequence of steps for using the systemillustrated in FIG. 1A; and

FIGS. 7A-7C illustrate a sequence of steps for using an alternativeembodiment of the system illustrated in FIG 1A, incorporating astabilizing suction head.

DETAILED DESCRIPTION OF THE INVENTION

The following detailed description should be read with reference to thedrawings in which similar elements in different drawings are numberedthe same. The drawings, which are not necessarily to scale, depictillustrative embodiments and are not intended to limit the scope of theinvention.

Refer now to FIG. 1A which illustrates a plan view of a catheter system10 in accordance with an exemplary embodiment of the present invention.Catheter system 10 includes a catheter 12 having an elongate shaft 14. Amanifold 16 is connected to the proximal end of the elongate shaft 14.The elongate shaft 14 includes a distal portion 18 which is illustratedin greater detail in FIG. 1B.

A pressurized fluid source 20 is connected to the catheter 12 by way ofthe manifold 16. Optionally, a vacuum source may be coupled to the sidearm of the manifold 16. The pressurized fluid source 20 may comprise aconventional syringe or an automated pressure source such as a highpressure injection system. An example of a high pressure injectionsystem is disclosed in U.S. Pat. No. 5,520,639 to Peterson et al. whichis hereby incorporated by reference. The system may be gas driven, suchas with carbon dioxide, or it may be mechanically driven, with a spring,for example, to propel the solution. Similarly, vacuum source 22 maycomprise a conventional syringe or other suitable vacuum means such as avacuum bottle.

Refer now to FIG. 1B which illustrates an enlarged detailed view of thedistal portion 18 of the elongate shaft 14. The distal portion 18 of theelongate shaft 14 includes a penetrating member 24 coaxially disposed inan elongate outer sheath 28. The penetrating member 24 contains aplurality of injection ports 26 disposed adjacent the distal endthereof. The injection ports 26 are in fluid communication with thepressurized fluid source 20 via penetrating member 24 and manifold 16.

With reference to FIG. 2, the penetrating member 24 includes a sharpeneddistal end 30 to facilitate easy penetration of tissue. The injectionports 26 extend through the wall of the penetrating member 24. Theinjection ports 26 each have an axis that is at an angle with thelongitudinal axis of the penetrating member 24. The axis of eachinjection port 26 may be orthogonal to the axis of the penetratingmember 24 or any other desired angle. The angle of the axis of eachinjection port 26 determines in part the penetration angle of the fluidas discussed in greater detail with reference to FIGS. 6A-6C.

With reference to FIG. 3, a lateral cross-sectional view taken alongline 3—3 in FIG. 2 is shown. The shaft 14 includes an annular lumen 36defined between the interior of the sheath 28 and the exterior of thepenetrating member 24. The annular lumen 36 may be used to infuse fluidsfor purposes of fluoroscopic visualization and/or aspiration.Alternatively, the annular lumen 36 may be used to facilitate theapplication of suction for stabilization purposes as will be discussedin greater detail with reference to FIGS. 7A-7C.

The elongate shaft 14 has characteristics (length, profile, flexibility,pushability, trackability, etc.) suitable for navigation from a remoteaccess site to the treatment site within the human body. For example,the elongate shaft 14 may have characteristics suitable forintravascular navigation to the coronary tissue from a remote accesssite in the femoral artery. Alternatively, the elongate shaft 14 mayhave characteristics suitable for transthoracic navigation to thecoronary tissue from a remote access point in the upper thorax. Thoseskilled in the art will recognize that the shaft 14 may have a widevariety of dimensions, materials, constructions, etc. depending on theparticular anatomy being traversed.

Refer now to FIG. 4 which illustrates a lateral cross-sectional viewtaken along line 4—4 in FIG. 2. Penetrating member 24 includes aninternal lumen 38 in fluid communication with the injection ports 26.The injection ports 26 are in fluid communication with the pressurizedfluid source 20 via lumen 38 of penetrating member 24 such that fluidmay be readily delivered from the pressurized fluid source 20 throughthe shaft 14 and into the heart tissue being treated. Fluidcommunication between the pressurized fluid source 20 and the injectionports 26 may be defined by a direct connection between the proximal endof the penetrating member 24 and the source 20 via manifold 16. Suchfluid communication may also be defined in part by an intermediate tubeconnected to the proximal end of the penetrating member 24.

The penetrating member 24 may have a length slightly greater than thelength of the outer sheath 28, with a penetrating length ofapproximately 1 to 10 mm. The inside diameter of the penetrating member24 should be sufficiently large to accommodate the desired flow rate offluid, but sufficiently small to reduce the amount of fluid wasteremaining in the lumen 38 after the procedure is complete. For example,the penetrating member 24 may have an inside diameter in the range of 1to 250 microns and an outside diameter in the range of 10 microns to1.25 mm. The penetrating member 24 may be formed of stainless steel orother suitable material such as nickel titanium alloy. The injectionports 26 may have a diameter ranging from approximately 1 to 500microns.

Refer now to FIGS. 6A-6C which illustrate operation of the cathetersystem 10. The heart tissue 60 (i.e., myocardium) may be accessed fromthe interior of the heart by, for example, navigating the catheter 12through the vascular system into a chamber of the heart. Alternatively,the heart tissue 60 may be accessed from the exterior of the heart by,for example, transthoracic minimally invasive surgery in which thecatheter 12 is navigated through the upper thoracic cavity adjacent theepicardium of the heart.

Regardless of the approach, the distal portion 18 of the catheter 12 ispositioned adjacent the desired treatment site of the heart tissue 60utilizing conventional visualization techniques such as x-ray,fluoroscopy or endoscopic visualization. While positioning the catheter12, the penetrating member 24 may be partially retracted in the outersheath 28 such that only the distal end 30 of the penetrating member 24is exposed, or fully retracted such that the entire penetrating member24 is contained within the outer sheath 28.

With the distal portion 18 positioned adjacent the heart tissue 60 asshown in FIG. 6A, the penetrating member 24 is advanced into the hearttissue 60 until the distal end 30 of the penetrating member 24 reaches asufficient depth to position the injection ports 26 completely withinthe tissue 60 as shown in FIG. 6B. This position may be confirmed byinjecting radiopaque contrast media or colored dye through the innerlumen 38 of the penetrating member 24 such that the contrast media ordye exits the injection ports 26.

Once in position, fluid 62 may be infused from the pressurized fluidsource 20 through the lumen 38 of the penetrating member and through theinjection ports 26 and into the heart tissue 60. After the fluid 62 hasbeen delivered via the injection lumens in the injection ports 26, thepenetrating member 24 may be retracted into the outer sheath 28. Afterretraction, the entire catheter 12 may be removed from the patient.

The pressure applied by the pressurized fluid source 20 to deliver thefluid 62 into the heart tissue 60 may vary depending on the desiredresult. For example, a relatively low pressure of approximately 0.01 to1 ATM may be utilized to deliver the fluid 62 into the heart tissue 60thereby minimizing trauma to the tissue adjacent the injection site.Alternatively, a relatively high pressure of approximately 10 to 300 ATMmay be utilized to increase the depth penetration of the fluid 62 intothe heart tissue 60 and/or to dispense the solution throughout theinjected tissue.

The penetration depth of the fluid 62 into the tissue 60 influencesfluid retention, the volume of tissue 60 treated and the degree oftrauma to the tissue 60. The penetration depth of the fluid 62 isdictated, in part, by the exit velocity of the fluid 62, the size of thefluid stream 62, and the properties of the tissue 60. The exit velocity,in turn, depends on the applied pressure of the pressurized fluid source20, the drag or pressure drop along the length of the lumen 38 and theports 26, and the cross-sectional area or size of the ports 26. The sizeof the fluid stream 62 also depends on the size of the ports 26. Thus,assuming the treatment site dictates the tissue 60 properties, thepenetration depth may be selected by adjusting the applied pressure ofthe pressurized fluid source 20, the size and length of the lumen 38,and the cross-sectional area of the ports 26. By adjusting theseparameters, fluid retention, treated tissue volume and degree of traumamay be modified as required for the particular clinical application.

As can be appreciated from the illustration of FIG. 6C, by injecting thefluid 62 in a direction different from the direction of penetration ofthe penetrating member 24, the fluid 62 will be retained within theheart tissue 60. Retention of the fluid 62 in the heart tissue 60 isprimarily accomplished by forming the injection ports at an anglerelative to the direction of penetration of the penetrating member 24,i.e., the longitudinal axis of the penetrating member 24. In addition toproviding better retention of the fluid 62 within the heart tissue 60,this arrangement also allows for a greater volume of heart tissue 60 tobe treated with a single primary penetration.

In an embodiment of the present invention, a low volume (severalmicroliters but less than 100 microliters by a single injection) ofsolution is delivered to the heart such that it may absorb the deliveredsolution within the time frame of the injection. In contrast to highervolume injections, the heart is more capable of absorbing these lowvolumes. The effect of the low volume injection is to minimize expulsionby the tissue. In order to deliver the entire dose of virus, it may bedesirable or necessary to concentrate the injection (i.e., deliver thesame number of viral particles or micrograms of protein, typicallydelivered in 100 μl, in a volume of 10 μl) or keep the concentration ofvirus the same as that typically used, but increase the number ofinjections from 10 (typical) to 20, 30, or more.

Each injectate may also be delivered in a prolonged manner such that theheart can absorb the solution as it is being injected (rate ofdelivery≦rate of tissue absorption). For instance, the injection can bedelivered at a defined flow rate using a syringe pump. The time ofinjection will depend on the volume to be delivered. For example, lowvolumes (a few microliters) may be delivered in under a minute whilehigher volumes (10 to 100 μl or more) may be delivered over severalminutes. In this instance, it may be beneficial to include a methodwhich gently attaches the injection catheter to the wall of the heart,for instance suction or vacuum.

Thus, to accomplish this result, the injection ports 26 may be formed atan angle to the longitudinal axis of the penetrating member 24.Preferably, the axes of the injection ports 26 are generally lateral tothe longitudinal axis of the penetrating member 24. However, the axes ofthe injection ports 26 may be formed at an angle of about 5 to about 90degrees relative to the axis of the penetrating member 24 to accomplishessentially the same result. Also preferably, the penetrating member 24penetrates the heart tissue 60 in a direction generally orthogonal tothe surface of the heart tissue 60 adjacent the injection site.

Refer now to FIGS. 7A-7C which illustrate operation of an alternativeembodiment of the catheter system 10. In this particular embodiment, thedistal portion of the catheter 12 incorporates a suction head 70connected to the distal head of the outer sheath 28. The suction head 70comprises a flexible tubular member having a generally conical shape.The suction head 70 has an interior which is in fluid communication withthe inner lumen 36 of the outer sheath 28. As mentioned previously, theinner lumen 36 of the outer sheath 28 is in fluid communication with thevacuum source 22. By actuating the vacuum source 22, suction is appliedto the suction head via the inner lumen 36 of the outer sheath 28.

The suction head is positioned adjacent the heart tissue 60 asillustrated in FIG. 7A. The suction head 70 grasps the surface of theheart tissue 60 thereby stabilizing the distal portion 18 of thecatheter 12. This is particularly beneficial when treating tissue in adynamic setting such as when the heart is beating. Absent a stabilizingmeans such as suction head 70, it maybe difficult to maintain the distalportion 18 in a relatively fixed position if the treatment site is notstationary. Those skilled in the art will recognize that otherstabilizing means may be utilized such as removable screw anchors,miniature forceps, etc.

After suction is applied to the suction head 70 thereby stabilizing thedistal portion 18 of the catheter 12, the penetrating member 24 isadvanced into the heart tissue 60 as illustrated in FIG. 7B. Once theinjection ports 26 of the penetrating member 24 are completely embeddedwithin the heart tissue 60, fluid 62 may be delivered into the hearttissue 60 via the injection ports 26 as discussed previously.

After the fluid 62 has been delivered to the heart tissue 60, thepenetrating member 24 may be retracted into the outer sheath 28. Afterretracting the penetrating member 24, the suction applied by the suctionhead 70 is terminated to release the distal portion 18 of the catheterfrom the heart tissue 60. The entire catheter system 12 may then beremoved from the patient.

From the foregoing, it is apparent that the present invention provides adevice and method for delivering and injecting fluid into heart tissueto improve delivery efficiency. This is accomplished by utilizinginjection ports which direct fluid in a direction different from thedirection of penetration of the penetrating member. Thus, fluid leakagefrom the injection site is reduced and the fluid is distributed over agreater volume of tissue.

Although treatment of the heart is used as an example herein, themedical devices of the present invention are useful for treating anymammalian tissue or organ. Non-limiting examples include tumors; organsincluding but not limited to the heart, lung, brain, liver, kidney,bladder, urethra and ureters, eye, intestines, stomach, pancreas, ovary,prostate; skeletal muscle; smooth muscle; breast, cartilage and bone.

The terms “therapeutic agents” and “drugs” are used interchangeablyherein and include pharmaceutically active compounds, cells, nucleicacids with and without carrier vectors such as lipids, compacting agents(such as histones), virus, polymers, proteins, and the like, with orwithout targeting sequences.

Specific examples of therapeutic agents used in conjunction with thepresent invention include, for example, proteins, oligonucleotides,ribozymes, anti-sense genes, DNA compacting agents, gene/vector systems(i.e., anything that allows for the uptake and expression of nucleicacids), nucleic acids (including, for example, recombinant nucleicacids; naked DNA, cDNA, RNA; genomic DNA, cDNA or RNA in anon-infectious vector or in a viral vector which may have attachedpeptide targeting sequences; antisense nucleic acid (RNA or DNA); andDNA chimeras which include gene sequences and encoding for ferryproteins such as membrane translocating sequences (“MTS”) and herpessimplex virus-1 (“VP22”)), and viral, liposomes and cationic polymersthat are selected from a number of types depending on the desiredapplication. Other pharmaceutically active materials includeanti-thrombogenic agents such as heparin, heparin derivatives,urokinase, and PPACK (dextrophenylalanine proline argininechloromethylketone); antioxidants such as probucol and retinoic acid;angiogenic and anti-angiogenic agents; agents blocking smooth musclecell proliferation such as rapamycin, angiopeptin, and monoclonalantibodies capable of blocking smooth muscle cell proliferation;anti-inflammatory agents such as dexamethasone, prednisolone,corticosterone, budesonide, estrogen, sulfasalazine, acetyl salicylicacid, and mesalamine; calcium entry blockers such as verapamil,diltiazem and nifedipine; antineoplastic/antiproliferative/anti-mitoticagents such as paclitaxel, 5-fluorouracil, methotrexate, doxorubicin,daunorubicin, cyclosporine, cisplatin, vinblastine, vincristine,epothilones, endostatin, angiostatin and thymidine kinase inhibitors;antimicrobials such as triclosan, cephalosporins, aminoglycosides, andnitorfurantoin; anesthetic agents such as lidocaine, bupivacaine, andropivacaine; nitric oxide (NO) donors such as lisidomine, molsidomine,L-arginine, NO-protein adducts, NO-carbohydrate adducts, polymeric oroligomeric NO adducts; anti-coagulants such as D-Phe-Pro-Argchloromethyl ketone, an RGD peptide-containing compound, heparin,antithrombin compounds, platelet receptor antagonists, anti-thrombinantibodies, anti-platelet receptor antibodies, enoxaparin, hirudin,Warafin sodium, Dicumarol, aspirin, prostaglandin inhibitors, plateletinhibitors and tick antiplatelet factors; vascular cell growth promotorssuch as growth factors, growth factor receptor antagonists,transcriptional activators, and translational promotors; vascular cellgrowth inhibitors such as growth factor inhibitors, growth factorreceptor antagonists, transcriptional repressors, translationalrepressors, replication inhibitors, inhibitory antibodies, antibodiesdirected against growth factors, bifunctional molecules consisting of agrowth factor and a cytotoxin, bifunctional molecules consisting of anantibody and a cytotoxin; cholesterol-lowering agents; vasodilatingagents; agents which interfere with endogeneus vascoactive mechanisms;survival genes which protect against cell death, such as anti-apoptoticBcl-2 family factors and Akt kinase; and combinations thereof.

Examples of polynucleotide sequences useful in practice of the inventioninclude DNA or RNA sequences having a therapeutic effect after beingtaken up by a cell. Examples of therapeutic polynucleotides includeanti-sense DNA and RNA; DNA coding for an anti-sense RNA; or DNA codingfor tRNA or rRNA to replace defective or deficient endogenous molecules.The polynucleotides of the invention can also code for therapeuticproteins or polypeptides. A polypeptide is understood to be anytranslation product of a polynucleotide regardless of size, and whetherglycosylated or not. Therapeutic proteins and polypeptides include as aprimary example, those proteins or polypeptides that can compensate fordefective or deficient species in an animal, or those that act throughtoxic effects to limit or remove harmful cells from the body. Inaddition, the polypeptides or proteins useful in the present inventioninclude, without limitation, angiogenic factors and other moleculescompetent to induce angiogenesis, including acidic and basic fibroblastgrowth factors, vascular endothelial growth factor, hif-1, epidermalgrowth factor, transforming growth factor α and β, platelet-derivedendothelial growth factor, platelet-derived growth factor, tumornecrosis factor α, hepatocyte growth factor and insulin like growthfactor; growth factors; cell cycle inhibitors including CDK inhibitors;anti-restenosis agents, including p15, p16, p18, p19, p21, p27, p53,p57, Rb, nFkB and E2F decoys, thymidine kinase (“TK”) and combinationsthereof and other agents useful for interfering with cell proliferation,including agents for treating malignancies; and combinations thereof.Still other useful factors, which can be provided as polypeptides or asDNA encoding these polypeptides, include monocyte chemoattractantprotein (“MCP-1”), and the family of bone morphogenic proteins(“BMP's”). The known proteins include BMP-2, BMP-3, BMP-4, BMP-5, BMP-6(Vgr-1) BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13,BMP-14, BMP-15, and BMP-16. Currently preferred BMP's are any of BMP-2,BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7. These dimeric proteins can beprovided as homodimers, heterodimers, or combinations thereof, alone ortogether with other molecules. Alternatively or, in addition, moleculescapable of inducing an upstream or downstream effect of a BMP can beprovided. Such molecules include any of the “hedgehog” proteins, or theDNA's encoding them.

The present invention is also useful in delivering cells as thetherapeutic agent. Cells can be of human origin (autologous orallogeneic) or from an animal source (xenogeneic), geneticallyengineered if desired to deliver proteins of interest at a delivery ortransplant site. The delivery media is formulated as needed to maintaincell function and viability.

Those skilled in the art will recognize that the present invention maybe manifested in a variety of forms other than the specific embodimentsdescribed and contemplated herein. Accordingly, departures in form anddetail may be made without departing from the scope and spirit of thepresent invention as described in the appended claims.

What is claimed is:
 1. A catheter for delivering a fluid to an injectionsite in heart tissue, comprising: a shaft having a proximal end, adistal end and an infusion lumen extending therein, the distal end ofthe shaft including a penetrating member having an injection port and asharpened distal end, wherein the penetrating member penetrates theheart tissue at the injection site in a first direction, and wherein theinjection port directs fluid in a second direction different from thefirst direction, said second direction is at an angle non-orthogonal andnon-parallel to infusion lumen such that fluid leakage from theinjection site is reduced.
 2. A catheter as in claim 1, wherein aplurality of injection ports are utilized.
 3. A catheter as in claim 2,wherein about 2 to about 100 injection ports are utilized.
 4. A catheteras in claim 2, wherein each of the plurality of injection ports have adiameter of approximately 1 to 500 microns.
 5. A catheter as in claim 1,wherein the second direction is generally lateral to the firstdirection.
 6. A catheter as in claim 5, wherein the first direction isgenerally orthogonal to the heart tissue at the injection site.
 7. Acatheter as in claim 1, further comprising a sheath disposed about theshaft.
 8. A catheter as in claim 7, wherein the sheath has a proximalend, a distal end and a lumen disposed therein.
 9. A catheter as inclaim 8, wherein the distal end of the sheath includes a suction head.10. A catheter as in claim 1, wherein the penetrating member has anouter diameter in the range of approximately 10 microns to 1.25 mm. 11.A catheter as in claim 10, wherein the penetrating member has an exposedlength in the range of approximately 1 to 10 mm.
 12. A catheter systemfor delivering a fluid to heart tissue, comprising: a pressurized fluidsource containing a fluid therein; and a catheter having a proximal end,a distal end and an infusion lumen extending therein, the proximal endof the catheter connected to the pressurized fluid source, the infusionlumen in fluid communication with the fluid contained in the pressurizedfluid source, the distal end of the catheter including an axialpenetrating member having a sharpened distal end and a plurality oflateral injection ports, each of the injection ports being in fluidcommunication with the infusion lumen such that fluid from thepressurized fluid source may be delivered to the heart tissue via theinjection ports, said ports further injecting fluid at a directionnon-orthogonal and non-parallel to the direction of the axialpenetrating member.
 13. A catheter system as in claim 12, wherein thepressurized fluid source is pressurized to a relatively low pressure ofless than approximately 1 ATM to reduce tissue trauma.
 14. A cathetersystem as in claim 12, wherein the pressurized fluid source ispressurized to a relatively high pressure of greater than approximately100 ATM to increase tissue penetration.
 15. A catheter system as inclaim 12, further comprising: a vacuum source; and a sheath disposedabout the catheter, the sheath having a proximal end, a distal end and asuction lumen disposed therein, the proximal end of the sheath connectedto the vacuum source with the suction lumen of the sheath in fluidcommunication with the vacuum source, wherein the distal end of thesheath is disposed adjacent the heart tissue such that the distal end ofthe sheath is stabilized against the heart tissue when a vacuum isapplied to the suction lumen using the vacuum source.
 16. A method ofdelivering a fluid to an injection site in heart tissue of a patient,comprising the steps of: providing a catheter comprising a shaft havinga proximal end, a distal end and an infusion lumen extending therein,the distal end of the catheter including a penetrating member, asharpened distal end, and an injection port; inserting the catheter intothe patient; navigating the catheter until the distal end of thecatheter is positioned adjacent the injection site; actuating thepenetrating member such that the sharpened distal end of the penetratingmember cuts the heart tissue at the injection site in a first direction;and injecting the fluid into the heart tissue via the injection port ina second direction said second direction non-orthogonal and non-parallelto the first direction.
 17. A method of delivering a fluid as in claim16, wherein less than approximately 100 microliters of fluid is injectedinto the heart tissue via the injection port.
 18. A method of deliveringa fluid as in claim 16, wherein the catheter includes a plurality ofinjection ports, and wherein fluid is injected into the heart tissue viathe injection ports.
 19. A method of delivering a fluid as in claim 18,wherein approximately 1 to 20 microliters of fluid is injected into theheart tissue via the injection ports.
 20. A fluid delivery mechanismcomprising: a sheath disposed about a catheter, the sheath having aproximal end, a distal end and a suction lumen, the proximal end of thesheath connected to a vacuum source with the suction lumen of the sheathin fluid communication with the vacuum source, the distal end of thesheath adapted to dispose adjacent to a body tissue such that the distalend of the sheath is stabilized against the body tissue when a vacuum isapplied to the suction lumen.